Colonoscopy is the endoscopic examination of the colon and the distal part of the small bowel with a CCD camera or a fiber optic camera on a flexible tube passed through the anus. It may provide a visualization of the colon and allows the physician to ascertain the presence of ulceration and/or polyps, and also provides the opportunity for biopsy of polyps or removal of suspected polyps/lesions. Colonoscopy is an important procedure for the screening, prevention and diagnosis of a number of diseases of the colon, especially colorectal cancer. In order to perform a useful colonoscopy, a complete evacuation of the contents of the bowel is required. In this regard, numerous purgative products have been developed for this purpose.
Adequate preparation of the colon is essential for complete colonoscopy with proper visualization of the mucosa. A great deal of effort has been devoted to improving the methods of colonic preparation. Polyethylene glycol has been used widely as a method for bowel cleansing, but leaves a significant percentage of patients receiving poorly prepared for their colonoscopy. This necessitates another bowel cleansing, and causes cancellation of the initially scheduled procedure, and in some cases cancellation of the procedure altogether by the patient.
While various methods of bowel preparation are used prior to colonoscopy, there is no general “gold standard” procedure. Useful bowel preparations are those that provide adequate visualization of the bowel with minimal patient discomfort or side effects. Most preferably, the bowel preparation must be acceptable to the patient. It should also preferably be inexpensive and easy for the patient to self-administer. In the past, both rectal and oral preparations, alone or in combination, have been used to cleanse the colon. Enemas have in the past been a preferred option because they quickly clear the bowel and require no dietary restrictions compared to oral preparations, however are not often used due to patient acceptability.
It has been established that adenomatous polyps are precursors of cancer, and that removal of these polyps can prevent colorectal cancer. For this reason, the development of screening methods for early detection of these established precursors of cancer has received increasing attention. These screening methods include computed tomographic (CT) colonography and magnetic resonance (MR) colonography.
Recent randomized trials comparing different methods of bowel preparations have considered the quality of bowel preparation as the focus of their study.
For example, Gidwani, et al., “A Prospective Randomized Single-blind Comparison of Three methods of Bowel Preparation for Outpatient Flexible Sigmoidoscopy”, Surg Endosc (2007) 21: 945-949 (Abstract published in Gastrointest Endosc 2004; (59(5): 127) reported a study concerning the performance of out-patient flexible sigmoidoscopy prospectively randomized to 3 groups: group 1: one Fleet enema 2 hours pre-procedure; group 2: two Fleet enemas, one on the evening prior to sigmoidoscopy and one 2 hours preprocedure; group 3: lactulose 30 ml orally 48 and 24 hours prior to sigmoidoscopy, plus a single Fleet enema 2 hours pre-procedure. A patient questionnaire was used to assess side effects and tolerance. There was no significant difference between the groups in terms of depth of insertion (p=0.42—chi-squared test) or abnormalities noted (p=0.34—chi-squared test). Nor was there any difference in the quality of preparation of patients in group 1 versus group 2 (p=0.39—Fishers exact test) or group 1 versus group 3 (p=0.13—Fishers exact). However, it was reported therein that lactulose+Fleet resulted in significantly fewer patients with acceptable preparation compared with those who administered two Fleet enemas (p=0.02—Fishers exact test). The authors concluded that the addition of a Fleet enema or oral lactulose over and above a single Fleet enema gives no significant improvement in the acceptability or efficacy of bowel preparation. This study further concluded that a single phosphate enema 2 hours pre-procedure is an effective method of bowel preparation for flexible sigmoidoscopy, and provides an acceptable quality of bowel preparation in approximately four of every five patients. The addition of a single phosphate enema or oral lactulose over and above this standard regimen was considered by the authors to be more costly and time consuming, and the addition of an extra enema or lactulose did not alter patient acceptability or quality of bowel preparation.
Florie, et al. “MR Colongraphy with Limited Bowel Preparation Compared with Optical Colonoscopy in Patients at Increased Risk for Colorectal Cancer” (Radiology: Volume 243, Number 1, April 2007) prospectively evaluated the diagnostic performance of magnetic resonance (MR) colonography by using limited bowel preparation in patients with polyps of 10 mm or larger in diameter in a population at increased risk for colorectal cancer, with optical colonoscopy as the reference. MR colonography was performed within 2 weeks prior to optical colonoscopy. All patients started preparation 48 hours prior to MR colonography with a low-fiber diet (only well-cooked, nonfibrous vegetables and meat, no fibrous fruit, no whole-wheat cereal products, no nuts), together with ingestion of 12 g of lactulose powder in 6-g packets (Lactulose CF; Centrafarm, Etten-Leur, the Netherlands) dissolved in water once per day (in the morning) for stool softening. An oral contrast agent that contained 10 ml of gadolinium in a dose of 0.5 mmol/ml (gadopentetate dimeglumine, Magnevist; Schering, Berlin, Germany) was added to all major meals during this period (6 meals over 2 days) for stool tagging. If the stool became too soft (diarrhea), patients were allowed to reduce the amount of lactulose. In a questionnaire, patients were asked about stool consistency prior to imaging and whether they reduced the amount of lactulose. Patients ingested 4-6 L of polyethylene glycol electrolyte solution (KleanPrep; Helsinn Birex Pharmaceuticals, Dublin, Ireland) for bowel preparation on the day before the examination (in patients who ingested 6 L, the last 2 L of that amount was ingested on the examination day). Optical colonoscopy was used as the reference standard. Optical colonoscopy was performed with a standard colonoscope. Of the 168 patients, 77 (38%) of the patients had diarrhea sometime during the bowel preparation; in 48 of these patients, diarrhea occurred just prior to imaging. Thirty seven patients reduced the amount of lactulose (all but one did so only on the last day). Prior to imaging in 191 patients, a spasmolytic agent was administered. One hundred forty-nine patients received butylscopolamine bromide, 42 received glucagon, and nine received no spasmolytic agent. On average, 1.9 L of water-gadolinium mixture was used to fill the colon. Two patients had considerable leakage; in 11, leakage was minor. MR colonography was well tolerated.
Florie, et al., “Feasibility Study of Computed Tomography Colonography Using Limited Bowel Preparation at Normal and Low-dose Levels Study” (Eur Radiol (2007) 17: 3112-3122) evaluated limited bowel preparation computed tomography colonography (CTC) using an oral contrast agent (amidotrizoic acid) in terms of image quality, patient acceptance and polyp visualization using conventional colonoscopy as a reference standard. Four weeks prior to the conventional colonoscopy, patients were asked to ingest amidotrizoic acid (20 mg/ml, made by the hospital pharmacy, 11.7 mg I/ml; corresponding to approximately 30 times diluted Gastrografin370®) three times a day (100 ml at breakfast and lunch, 300 ml at dinner) with a low-fiber diet (well cooked vegetables and meat, no fibrous fruit, no whole-wheat products, no nuts) starting 2 days prior to CTC. Lactulose (12 g, lactulose CF powder 6 g/sachet, Centrafarm, Etten-Leur, The Netherlands) was taken in the morning for 3 days prior to CTC for stool softening. Twenty mg of butylscopolaminebromide (Buscopan; Boehringer-Ingelheim, Ingelheim, Germany), when contraindicated, 1 mg of glucagon hydrochloride (Glucagen; Novo-Nordisk, Bagsvaerd, Denmark) was administered intravenously. The colon was insufflated with a CO2-air mixture (13.2% vol.) using a flexible catheter until patients experienced discomfort (±2-3 l). Patients were scanned in prone and supine position with a four-sliceMX8000 (PhilipsMedical Systems, Best, The Netherlands) CT scanner (120 kV, rotation time 0.75 s, pitch 1.25, collimation 4*2.5 mm, section thickness 3.2 mm, and reconstruction interval 1.6 mm, 50 or 70 milliampere-second (mAs); 70 mAs if the abdominal circumference was >102.5 cm, scan time 20-25 s). Prior to CC, each patient was instructed to ingest 41 of a macrogol solution (Colofort macrogol 4000 sachets, Ipsen, Hoofddorp, The Netherlands), starting on the evening prior to the CC. The authors took the position that the study demonstrated that CTC without cleansing is preferred to colonoscopy and shows moderate sensitivity (60-67%) for polyps of at least 10 mm in size without impaired diagnostic value at mSV levels as low as 0.7 mSv.
Florie, et al. “MR Colonography With Limited Bowel Preparation” (Radiology Volume 245: Number 1, October 2007) evaluated magnetic resonace (MR) colonography with limited bowel preparation compared with full-preparation colonoscopy in participants at increased risk for colorectal cancer. All participants were prepared with a low-fiber diet, lactulose, and an oral contrast agent 48 hours before MR imaging. All were sent a list summarizing what dietary measures were necessary (no fiber-rich food, no nuts). The lactulose (12 g Lactulose CF powder [6 g per sachet]; Centrafarm, Etten-Leur, the Netherlands) was dissolved in water and taken both days before MR colonography in the morning for stool softening. If the stool became too soft, participants were allowed to reduce the amount of lactulose (asked in questionnaire 2). Ten milliliters of a gadolinium chelate (gadopentetate dimeglumine 0.5 mmol/mL, Magnevist; Schering, Berlin, Germany) was added to all major meals during this period (six meals over 2 days) for stool tagging. Questions about stool consistency (diarrhea, soft stool, normal shaped), abdominal pain (yes, no), and flatulence (yes, no) were asked in questionnaire 2. Participants ingested 4 L of polyethylene glycol electrolyte solution (Klean-Prep; Helsinn Birex Pharmaceuticals, Dublin, Ireland) for bowel preparation the day before conventional colonoscopy (if the examination was performed in the morning) or 2 L on the day before and 2 L on the day of the examination (if the examination was performed in the afternoon). If necessary, additional solution was ingested. Participants were not allowed to eat after starting the bowel preparation. The colonoscopy was performed with a standard scope. The authors concluded that the study results showed that most (65%) participants at increased risk for colorectal cancer prefer MR colonography with limited bowel preparation to colonoscopy for their next examination when there is a 20% chance of having to undergo a therapeutic colonoscopy afterwards. In a questionnaire completed at home at least 5 weeks after the procedures, fewer participants preferred MR colonography, but most (65%) still preferred MR colonography with limited bowel preparation. This preference was mainly based on the limited bowel preparation necessary for MR colonography and the fact that less pain was experienced during MR colonography. Filling of the colon with water and the multiple breath holds necessary were considered the most burdensome factors of MR colonography.
Urita, et al. “Hydrogen Breath Test as an Indicator of the Quality of colonic Preparation for Colonoscopy” (Gastrointestinal Endoscopy Vol. 57, No. 2, 2003), reported the results of a study where patients undergoing colonoscopy were instructed (after fasting overnight) to ingest a polyethylene glycol solution containing 12 g lactulose at a rate of 50 ml every 5 minutes for 2 hours. The preparation for colonoscopy was judged to be poor in 18% and adequate in 82% of the patients.
U.S. Pat. Nos. 7,718,197 and 7,687,075 (Skiendzielewski, et al.) describe colonic purgative compositions in a solid tablet dosage form, comprising at least one purgative (e.g., sodium phosphate or lactulose) and at least one soluble, nonfermentable binder, such as polyethylene glycol. The compositions are designed to improve patient tolerance and compliance, while at the same time improving the quality of bowel cleansing prior to diagnostic and surgical procedures and are said to be useful in lower dosages as a laxative to promote elimination and/or to relieve constipation.
Due to their efficacy in constipation, prescription osmotic laxatives like Kristalose®, the dry powder form of lactulose marketed by Cumberland Pharmaceuticals Inc., have received some attention from gastroenterologists for use as a bowel evacuant prior to colonoscopy, but these effects have not been formally studied or documented. Patients reportedly regard this bowel preparation regimen as being more tolerable than traditional regimens. Kristalose is an FDA-approved drug for the treatment of chronic constipation and is a generic version of lactulose which has been in use for more than 30 years.
Currently, there are multiple purgatives approved for bowel evacuation prior to colonoscopy and these products are often described as foul tasting, harsh, and too voluminous. Therefore, a product and regimen that is more acceptable to patients would be beneficial. A more palatable and convenient process may increase patient compliance and satisfaction.